Maternal neutralizing antibodies (NAbs) may play a role in determining whether an infant becomes infected during Mother to Child Transmission (MTCT). Higher levels of both autologous and heterologous NAbs are associated with non-transmission. Although single-dose or multiple-dose nevirapine has limited transmission dramatically, there is growing concern over the development and persistence of drug-resistant viruses in the infants that could limit future treatment, raising interest in testing vaccines or immunotherapies during the early breastfeeding period, when postpartum transmission risk is highest. The focus of this renewal is to expand on the findings of the first funding period. We established a perinatal SHIV transmission model in M. nemestrina, where we have evidence for extraordinary virus control in infected and exposed newborn macaques. This model allows a detailed analysis of transmitted variants, passive transfer of maternal IgG and NAbs, and the development of autologous de novo responses in newborns. We plan to explore the role of preexisting NAbs in limiting infection and facilitating de novo antiviral immunity. We hypothesize that the presence of moderate to high levels of NAbs (IgG) at the time of oral SHIV exposure will limit infection or pathogenesis in newborns by reducing the infectivity or number of variants that are transmitted. To test this concept, we will challenge newborns orally with SHIV in the presence of NAbs that are closely matched to the challenge virus versus mismatched NAbs. We will compare the development of de novo responses to SHIV with responses to hepatitis B vaccine given to the infant macaques in the absence of passive immunity. Understanding the potential and limitations of natural immunity will aid in the conceptual and optimal design of vaccines and immunotherapies that can further limit MTCT. 1. Characterize the transmitted viruses and the de novo antiviral responses in exposed infants with highly controlled SHIV infection and determine their profiles of neutralization sensitivity and resistance to passively acquired maternal IgG. 2. Test the antiviral effects of IgG (SHIVIG) as a model for maternal antibodies in limiting infection, by comparing neutralizing IgG matched to the challenge virus versus mismatched IgG with limited or no neutralizing activity against the challenge virus. 3. Determine whether the presence of neutralizing versus non-neutralizing IgG affects the magnitude or timing ofde novo NAbs in infected infants. Investigate possible mechanisms of action in the development of accelerated NAb responses and other antiviral immune responses.